Process for production of



United States Patent Ofilice 3,l96,l48 Patented July 20, 1965 3,196,146PROCESS FUR PRUDUtITlQN 01F 3-NlTRtl-5- ACYL-IMINODIEENZYL RobertAlbrecht and Henri Dietrich, Arlesheini, Basel- Land, and FridoiinHefti, Riehen, Switzerland, assignors to Geigy Chemical Corporation,Greenhurgh, N.Y., a corporation of Delaware No Drawing. Filed Aug. 20,1964, Ser. No. 3%,991 Claims priority, application, Switzerland, Dec.22, 1960, 14,297/60, 14,298/60 1 Claim. (Cl. 260239) This is acontinuation-in-part of our copending application, Serial No. 161,250,filed December 21, 1961.

The present invention concerns a new process for the production of nitroderivatives of S-acyl-imino-dibenzyls. These compounds are valuableintermediate products for the synthesis of the corresponding 3-aminocompounds, which have antioxidant properties. These amino compounds canalso be used as intermediate products for the synthesis ofpharmaceuticals.

On nitrating dibenzoheterocyclic compounds having an irnino group asheterocyclic ring member such as carbazole, phenoxazine andphenothiazine, first one or two nitro groups enter into one or bothbenzene nuclei in the para-position to such imino group, in the case ofphenothiazine mono-oxidation of the sulphur atom occurs simultaneously.T his disposition to occupy the paraposition is further increased onacylation of an amino or imino group.

Surprisingly it has now been found that 3-nitro-5-acyl imino-dibenzylcompounds or" the formula I acyl wherein Acyl is an acyl radical, e.g.,a lower alkanoyl radical as, for instance, acetyl, propionyl,isobutyryl, butyryl, valeroyl or isovaleroyl and furthermore a radicalof an aromatic acid as for instance benzoyl can be produced by treatinga S-acyl-iminodibenzyl, e.g. 5-acetyl-iminodibenzyl, with substantiallythe equimolar amount of nitric acid in sulfuric acid. The nitro group inthis reaction enters into the meta position of the acylimino group ofthe condensed heterocyclic ring system.

For the nitration, j-acetyl-iminodibenzyl, for example, or anotherS-acyl-iminodibenzyl is dissolved in ten to twenty times its weight ofconcentrated sulfuric acid and 0.9-1 mol of concentrated nitric acid (40B.) per mol of 5-acyl-iminodibenzyl in concentrated sulfuric acid areadded dropwise at temperatures between about 10 and +10 0., preferablybetween about and about +C. The crude product, obtained by precipitationfrom the reaction solution with ice, is subjected to fractionalcrystallization, e.g., from benzene, ethanol or methanol, whereupon3-nitro-S-acyl-iminodibenzyl is obtained. The3-11itro-5-acetyl-iminodibenzyl crystallizes as colorless prisms whichmelt at 157l58 C.

These above-given reaction conditions are critical; they lead torelatively pure 3-nitro-S-acyldminodibenzyls, which can be separated bysimple crystallization from the reaction mixture. If one deviates fromthese reaction conditions, e.g., by working at a higher temperature orwith more nitric acid, and increasing amout of 3,7-dinitro-5-acyl-iminodibenzyl is obtained from which the 3-nitroproduct cannot beseparated in a manner suitable for carrying out the process on anindustrial scale.

The 3-nitro-5-acyl-iminodibenzyls are reduced advantageously by means ofiron and acetic acid or hydrochloric acid according to Bchamp; however,other reduction processes such as e.g., treatment with zinc and aceticacid, and also catalytic hydrogenation, e.g., in the presence of Raneynickel, can also be employed.

3amino-5-acyliminodibenzyls, in particular 3-amino-S-acetyl-iminodibenzyl, are valuable intermediate products for theproduction of iminodibenzyl derivatives which can be used fortherapeutical purposes as they can be diazotized and the diazonium saltscan be converted into E-substituted iminodibenzyls and iminostilbenessuch as, for example, the 3-chloro-, 3-brorno-, 3-hydroxyand3-methoxyderivatives. From these, substances having particularpsycho-pharmacological properties, e.g., antidepressive activity, areobtained, for example, by introduction of dialkylaminoalkyl radicalsinto the 5- position, e.g., the y-dimethylaminopropyl radical or'ydimethylamino-fi-methylpropyl radical.

Up to now, 3-amino 5-acetyl-iminodibenzyl has been produced, e.g., fromiminodibenzyl by a rather long chain of reactions, namely acetylation tothe 5-acetyl-iminodi benzyl, introduction of the 3-acetyl group into thelatter by means of acetyl chloride in the presence of aluminium chloridein carbon disulfide, conversion of the 3,5-diacetyliminodibenzylobtained into 3-acetamido-S-acetyl-iminodibenzyl by treatment withhydrazoic acid according to Schmidt, and hydrolytic liberation of theS-arnino group with retention of the S-acetyl radical.

The nitr o derivatives of fi-acyl-iminodibenzyls according to theinvention represent therefore easily accessible intermediate productsfor the production of the above mentioned S-amino-S-acyl-iminodibenzyls.

The following examples further illustrate the processes according to theinvention without restricting the invention to the given examples.Unless otherwise stated, parts are given as parts by weight and therelationship of parts by weight to parts by volume is as that of grammesto cubic centimeters. Degrees are given in degrees centigrade.

Example 1 237 parts of S-acetyl-irninodibenzyl are dissolved at roomtemperature in 3500 parts of concentrated sulfuric acid and a mixture ofparts of nitric acid, 40 B6. (0.95 mol) and 400 parts of concentratedsulfuric acid is added dropwise to the solution while stirring at 0-5".The reaction solution is stirred for 30 minutes at 0 and then pouredinto about 6000 parts of ice. The crystals which precipitate arefiltered oif under suction and washed neutral with water. The moistfilter product is dissolved in 1000 parts by volume of benzene, thewater is removed and 500 parts by volume of the benzene solution aredistilled off. The solution which remains is cooled to 5, theprecipitated crystals are filtered oil under suction, washed with alittle cold benzene and dried. About 112 parts of3-nitro-5-acetyl-irninodibenzyl (4-0, and even 45 50% theor.) areobtained. The product can also be worked up by dissolving the moistfilter residue in 1000 parts by volume of hot 95% ethanol or hotmethanol, then distilling off 500 parts by volume of the solvent,letting the concentrated solution stand at about 20, filtering off theprecipitated crystals under suction and washing with a little ethanol ormethanol and drying.

The yield of pure substance is the same as that obtained by the firstmethod.

The pure 3-nitro-5-acetyl-iminodibenzyl melts at 157- 158,recrystallized from benzene, ethanol or methanol.

Example 2 In an analogous manner, starting with 251 parts of5-propionyl-iminodibenzyl, MP. 68-70, instead of the w 237 parts ofS-acetyl-iminodibenzyl in Example 1, 3-nitro- 5- propionyl-iminodibenzylis obtained, which can be recrystallized from ethanol or methanol, andwhich melts at 165-166.

Starting with 299 parts of S-benzoyl-iminodibenzyl, M.P. 126l27, theproduct obtained is 3-nitro-5-benzoyl-iminodibenzyl, M.P. 178180, andstarting with 279 parts of S-isovaleroyl-iminodibenzyl, M.P. 6667, theproduct obtained is 3-nitro-5-isovaleroyl-iminodibenzyl, M.P. 115-116".

We claim:

A process for the production of 3-nitro-5-acyl-iminodibenzyl of theformula acyl wherein acyl is a member selected from the group consistingof acetyl, propionyl, butyryl, isobutyryl, valeroyl, isovaleroyl andbenzoyl,

comprising (a) dissolving N-acyl-iminodibenzyl wherein acyl has theforegoing meaning, in a sufiicient amount of concentrated sulfuric acid;

(b) cooling the reaction mixture to a temperature in the range of l0 C.to +10 C., and, while maintaining the mixture at said temperature,slowly adding thereto while stirring at substantiallyequimolar amount ofa mixture of 40 B. nitric acid and concentrated sulfuric acid in avolume ratio of about 1:4;

(c) pouring the reaction mixture on an amout of ice being at least equalto that of the sulfuric acid in said mixture; and

(d) recovering the compound of the above formula from the resultingsolution.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

